An oxazoline analogue and an oxazine analogue have broad usages including medicines, agrochemicals, optical recording materials and the like, and anticancer activity and diabetes treatment effect of an oxazoline derivative receive attention in recent years.
Various synthesis methods for an oxazoline compound have been known. An oxazoline ring has three regioisomers, and among these, a synthesis method for a 2-oxazoline compound has been best known.
Typical production methods for a 2-oxazoline compound include (1) a method of reacting an alkali, triethylamine, acetic anhydride or ethyl orthoformate to an N-(2-haloethyl)carboxylic amide derivative, (2) a method of subjecting N-(2-hydroxyethyl) carboxylic amide to dehydration ring-closing reaction by heating with concentrated sulfuric acid or thionyl chloride, (3) a method of heating a carboxylic acid and 2-aminoethanol along with an alumina catalyst, (4) a method of heating a nitrile compound and 2-aminoethanol in the presence of a strong base, such as sodium methoxide and the like, or by using calcium chloride as a base, (5) a method of heating an acid imide ester and 2-aminoethanol along with alumina, or acting an alkali or sulfuric acid to an imino ester of 2-haloethanol, and (6) a method of heating an acyl derivative of an unsaturated amine with a mineral acid, such as sulfuric acid, hydrochloric acid or the like. Various modified methods can be considered for the aforementioned methods, and other raw materials may be used. For example, in the methods (1) and (2), a thiocarboxylic acid amide can be used instead of an acid amide, and a 2-thiazoline compound is obtained in this case.
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Accordingly, various kinds of 2-oxazoline compounds can be conventionally produced, and a 2-oxazoline compound having an intended substituent can be produced by selecting a reactant having a suitable substituent. For example, reaction of a 1,2-substituted 2-aminoethanol and a carboxylic acid compound or a nitrile compound can be considered. However, there are often cases where completely no reaction proceeds or cases where severe reaction conditions are needed and unfavorable reaction results are provided, depending on the substituent. Accordingly, there is difficulty in synthesis of a compound having substituents on the 2-, 4- and 5-positions of an oxazoline ring, and it is necessary to provide another measure different from the conventional ones for obtaining a 2-oxazoline compound having an intended substituent.
There are the similar situations for a thiazoline compound, an oxazine compound, a thiazine compound and the like, which are analogue compounds thereof. Specifically, there is no versatile method found for synthesizing an oxazoline analogue or an oxazine analogue having an arbitrary substituent under mild conditions, and a simple synthesis method is being demanded.    Non-patent Document 1: Gabriel Heymann, Chem. Ber., 23, 1890, 2502    Non-patent Document 2: Wenker, J. Am. Chem. Soc., 57, 1935, 1079    Non-patent Document 3: W. Seeliger, Angev. Chem. GE, 78, 20, 1966, 913-927    Non-patent Document 4: W. O, Siegel, J. Org. Chem., EN, 42, 11, 1977, 1872-1877    Non-patent Document 5: Boualem Oussaid, et al., Synth. Commun., EN, 25, 5, 1995, 659-666    Non-patent Document 6: S. Gabriel, R. Stelzner, Chem. Ber., 28, 1895, 2929    Patent Document 1: German Patent No. 2,158,615